iwCLL 2025 | Characteristics of patients with CLL who develop immunity following vaccination on BTKi therapy

So this is some really interesting work that’s come about because of IMPROVE. So the results from the IMPROVE trial showed that actually two-thirds of patients were able to generate an antibody response, and that had no reflection on whether they’d paused the drug or not. And actually, when we’ve looked at those antibody responses a little bit more, we can see that they’re really highly functional responses in many of the patients so they neutralize the virus in live culture very well and they have class switch antibody responses. And so that suggested that there are you know two-thirds of patients that even whilst they take a covalent BTK inhibitor are able to generate meaningful antibody responses, and we weren’t aware of that really before we started the trial. 

And so what we’ve been trying to understand is what are the characteristics of those patients that are able to generate immunity on drug compared to those who can’t. And one of the things that’s come through is that actually on drug, these patients can signal through their B-cell receptors and undergo what we think is a germinal center reaction to get these high affinity antibody responses. So it’s not the drug itself stopping them from generating antibodies. It’s actually the presence of normal B-cells in the first place. And that seems to be different depending on the time that we’re starting therapy on these patients. And so we’re generating data now to try and identify really who we think is going to be at high risk of infections on these drugs, but also those that can’t respond to vaccination. 

The other thing, just to point out as well, because we haven’t talked about it, but the cellular immune system, so the other half of our immune system, we’ve also been studying, and like others have shown on covalent BTKis, that the functional responses of T-cells is actually very good. So the IMPROVE trial recruited both patients on ibrutinib and acalabrutinib. And so we were able to do a comparison. And it was around 50-50, actually, in each of those drug groups. And so we could see the previously reported descriptions of the difference in the Th1 and Th2 responses for patients who take ibrutinib compared to acalabrutinib, that was clear. But actually, if you look at the ability to mount a T-cell response following the vaccination, there was no difference between those that took ibrutinib or acalabrutinib. But generally, overall, the vast majority of patients on a covalent BTK inhibitor were able to generate a T-cell response against SARS-CoV-2 and the spike antigen that was in the vaccine. So that’s a good message, we think, and important for patients to make sure that they are continuing to get boosters when they’re offered, because even where they weren’t able to get antibody responses, they were able to generate very good cellular responses on these drugs.

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